Human umbilical mesenchymal stem cell-derived mitochondria ameliorate maternal phenotype by improving placental mitochondria and vascular function in angiotensin II-induced preeclampsia rat

ABSTRACT Background Mitochondrial transplantation (Mito-T) is a novel therapeutic strategy targeting ischemic cardiovascular diseases. Here, we tested the efficacy of human umbilical mesenchymal stem cell-derived mitochondria transplantation (Mito-T) on a rat model of PE. Methods PE was induced by infusing angiotensin II (Ang II) to SD pregnancy rats on gestation day 8 (GD 8). Mito-T (100 μg/μl) was injected via jugular vein on GD 14. Findings On GD 20, PE rats showed high blood pressure, kidney and placental vascular abnormalities, reduced placental and fetal weights. Injected Mito-T was distributed intensively in the kidney, uterus and placenta of PE rats. Importantly, Mito-T reversed clinical manifestations of PE, restored placental abnormalities and reduced serum sFLT-1 levels and sFLT-1/PlGF ratio. In the placental mitochondria, Mito-T increased ETC complexes (complex I-V), improved mitochondrial membrane potential, ATP synthase and citrate synthase activities and biogenesis markers (PGC-1α, TFAM, NRF1) and reduced ROS production. Mito-T increased mitochondrial fusion proteins (OPA1, MFN1 and MFN2), reduced mitochondrial fission proteins (DRP1 and FIS1) and mitophagy proteins (PINK, BNIP3, BNIP3L, FUNDC1), restored sFLT-1 regulating calcineurin-NFAT-dependent pathways in the placental tissue, primary trophoblast cells and Bewo cell line. Furthermore, eNOS, nNOS and AT2R mRNA and protein expressions were restored in placenta and trophoblast cells after Mito-T. Interpretation This is the first study of PE treatment with Mito-T. Mito-T reverses pathological phenotypes of PE rats by improving placental mitochondrial and vascular function. The results provide proofs of concept of Mito-T as a potential therapeutic strategy for reducing maternal and fetal risks in PE patients. Funding This work is supported by Korean National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A2C1005720, NRF-2023R1A2C1005720), BK21 FOUR education program, Korean Society of Hypertension (Grant number KSH-R-2020), National Natural Science Foundation of China (NSFC 31660284, NSFC31860288).